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The biological effect and the mode of action of the CXCL7-CXCL12 chemokine heterodimer

CXCL7-CXCL12趋化因子异二聚体的生物学效应和作用方式

基本信息

批准号：
10730914
负责人：
Irina V Nesmelova
金额：
$ 46.2万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730914
关键词：
Adhesions Affect Atherosclerosis Autoimmune Diseases Award Binding Biological Biological Assay Biology Biophysics Blood Platelets CXCR4 Receptors CXCR4 gene Cell Migration Induction Cell surface Cells Development Disease Disulfides Endothelium Environment Future G-Protein-Coupled Receptors Glycosaminoglycans HIV/AIDS Health Heterodimerization Homo Human IL8RB gene Individual Infection Institution Interleukin-8B Receptor Intervention Knowledge Malignant Neoplasms Mediating Methods Molecular Nature Outcome PPBP gene Public Health Regulation Research Role Signal Induction Signal Transduction Stromal Cell-Derived Factor 1 Wages Western Blotting cell motility chemokine graduate student in vivo insight intermolecular interaction migration monomer neutrophil novel therapeutic intervention response screening structural biology training opportunity undergraduate student

项目摘要

ABSTRACT Chemokines are essential in health and disease such as infections, autoimmune diseases, atherosclerosis, HIV/AIDS, and cancer. Many chemokines engage in heterophilic interactions with each other to form heterodimers, leading to synergistic activity enhancement or reduction dependent on the nature of heterodimer- forming chemokines. The mode of action of chemokine heterodimers remains poorly understood. Previously, we identified all platelet-derived chemokines interacting with the two most abundant platelet chemokines, CXCL4 and CXCL7. The CXCL12 chemokine demonstrated strong heterodimerization with CXCL7. In the current project, we will determine the biological consequences of these new interactions and the mode of action of the CXCL7-CXCL12 heterodimer. In aim 1, we will determine the effect of CXCL7-CXCL12 heterodimerization on CXCL12-mediated activities, that the CXCL7-CXCL12 heterodimer binds and activates the CXCL12’s receptor CXCR4, and the molecular mechanism underlying the effect of the CXCL12-based heterodimers on cell migration. In aim 2, we will determine the effect of CXCL7-CXCL12 heterodimerization on CXCL7-mediated activities (neutrophil adhesion and migration) and the involvement of the CXCR2 receptor in CXCL7-CXCL12 heterodimer-mediated activities. The results of this project will deepen our understanding of chemokine biology and inform the future development of novel therapeutic intervention strategies exploiting heterophilic chemokine interactions.

摘要趋化因子在健康和疾病如感染、自身免疫性疾病、动脉粥样硬化，艾滋病和癌症。许多趋化因子参与异嗜性相互作用，异二聚体，导致依赖于异二聚体的性质的协同活性增强或降低。形成趋化因子。趋化因子异源二聚体的作用方式仍然知之甚少。此前我们鉴定了所有与两种最丰富的血小板趋化因子CXCL 4相互作用的血小板衍生趋化因子 CXCL7 CXCL 12趋化因子表现出与CXCL 7的强异源二聚化。在当前项目，我们将确定这些新的相互作用的生物学后果和作用模式， CXCL 7-CXCL 12异二聚体。在目的1中，我们将确定CXCL 7-CXCL 12异二聚化对CXCL 12表达的影响。 CXCL 12介导的活性，CXCL 7-CXCL 12异二聚体结合并激活CXCL 12的受体 CXCR 4，以及基于CXCL 12的异源二聚体对细胞增殖的影响的分子机制迁移在目标2中，我们将确定CXCL 7-CXCL 12异二聚化对CXCL 7介导的细胞凋亡的影响。活性（中性粒细胞粘附和迁移）和CXCL 7-CXCL 12中CXCR 2受体的参与异二聚体介导的活性。该项目的结果将加深我们对趋化因子生物学的理解并为未来开发利用异嗜性趋化因子的新型治疗干预策略提供信息交互.